Work

Vitamin D receptor in osteoblast lineage cells mediates increased sclerostin circulation and decreased bone formation in hypervitaminosis D

Year: 2025

Type: article

Abstract: Hypervitaminosis D is induced iatrogenically or endogenously. We previously reported that the vitamin D receptor (VDR) in osteoblast lineage cells mediates bone resorption and soft-tissue calcification in hypervitaminosis D. However, bone formation in hypervitaminosis D remains understudied. Here, we show that abundant 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] suppresses bone formation through VDR in osteoblast lineage cells. High-dose 1,25(OH) 2 D 3 suppressed bone formation and increased serum sclerostin, a bone formation inhibitor, in Control but not osteoblast lineage-specific VDR-cKO [ Osterix (Osx)-VDR-cKO ] mice. However, Sost mRNA expression in bone was downregulated by 1,25(OH) 2 D 3 in Control but not Osx-VDR-cKO mice. Meanwhile, mRNA expression of β-1,4-N-acetyl-galactosaminyltransferase 3 (B4GALNT3), whose function is reported to decrease circulating sclerostin, was suppressed by 1,25(OH) 2 D 3 in bone in Control but not Osx-VDR-cKO mice. Overexpressed B4galnt3 in rodent osteoblast-lineage cell lines increased GalNAcβ1→4GlcNAc- (LDN-) glycosylated sclerostin, suggesting that this modification can explain the discordance between serum sclerostin levels and mRNA in bone. Although excessive 1,25(OH) 2 D 3 increased mRNA levels of Fibroblast growth factor 23 ( Fgf23) , another osteotropic factor, by 10-fold through VDR in osteoblast lineage cells, it was previously shown to increase serum FGF23 levels by several hundred-fold. 1,25(OH) 2 D 3 -induced changes of FGF23-degradation regulators, such as furin, polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), and family with sequence similarity member 20 C (FAM20C), did not match the markedly high FGF23 levels, suggesting the existence of other regulators of FGF23. These findings suggest that VDR plays pivotal roles in the suppression of bone formation in hypervitaminosis D, possibly by increasing circulations of sclerostin and FGF23 through post-translational or post-transcriptional mechanisms. • High-dose 1,25(OH) 2 D 3 inhibits bone formation via VDR in osteoblast lineage cells. • 1,25(OH) 2 D 3 increases serum sclerostin levels via VDR in osteoblast lineage cells. • 1,25(OH) 2 D 3 decreases B4galnt3 mRNA levels through VDR in osteoblast lineage cells. • Sclerostin LacdiNAcylated by B4GALNT3 is prone to be secreted from osteocytes.

Source: The Journal of Steroid Biochemistry and Molecular Biology

DOI: 10.1016/j.jsbmb.2025.106711